Vaccines against nicotine, cocaine, opiates, and PCP have been proposed as treatments for drug abuse. By eliciting anti-drug antibodies in the plasma, these vaccines sequester drugs in the blood and thereby block their entry into the brain. Without the CNS effects as positive feedback for drug abuse, the effectiveness of drug abstinence programs is markedly improved. In clinical trials of nicotine and cocaine vaccines, however, the only subjects who were helped were those with very high antibody levels. Fully two-thirds of the subjects failed to reach this high level of antibodies and correspondingly failed to maintain drug abstinence. The reason for this impasse is a roadblock in vaccine design: as small molecules, drugs must be conjugated to a carrier in order to elicit an antibody response. Because the carrier is also immunogenic, part of the antibody response is diverted toward the carrier, rather than being directed against the drug. Studies in animals support the concept that blocking the response to the carrier will result in much higher antibody levels against the drug (called a "hapten" in this context). Consequently, this project will explore a novel approach to vaccination which works in two stages: a first "subtraction vaccination" is used to deplete off-target, anti-carrier B cells;a following "selection vaccination" is used to raise antibodies specifically directed against the drug hapten target. This approach, which we call "precision immunization," is anticipated to produce unprecedented levels of anti-drug antibodies that will be high enough to promote drug abstinence in the majority of recipients. PUBLIC HEALTH RELEVANCE: Cigarette smoking remains the leading preventable cause of death in the U.S. and accounts for about 1 of every 5 deaths (438,000 people) each year. Vaccines against nicotine could help individuals achieve abstinence, but the current vaccines are not yet strong enough to be effective. By developing a new approach to vaccination, this project will enhance these existing vaccines so that they are able to help patients.